Extensive research in the past 50 years has demonstrated that Dental caries is a microbial infection caused by a limited number of cariogenic bacteria (i.e., Streptococcus mutans) that co-reside with over 400 other non-harmful/commensal microbial species in the Dental plaque. The current anti-microbial strategies used to treat Dental caries have consisted primarily of mechanical removal of Dental plaque or generalized killing of oral bacteria with anti-bacterial compounds. These "remove all, kill-all" approaches have shown limited efficacy, since a "cleaned" tooth surface provides an equal opportunity for commensal and pathogenic bacteria to re-colonize in the non-sterile environment of the oral cavity. Cariogenic bacteria usually re-dominate the Dental plaque after the treatment and start another cycle of cariogenesis. This study proposes to develop a targeted antimicrobial therapy against Streptococcus mutans. By selectively killing or inhibiting the cariogenic bacteria within a pathogenic Dental plaque, a non-pathologic, commensal microbial community could be established. This "healthy plaque" would then serve as an effective barrier to prevent the subsequent colonization of cariogenic bacteria on the tooth surface, leading to a sustained anti-caries therapeutic effect. With the Phase-I funding support, a new class of S. mutans-selective molecules, called specifically (or selectively) targeted antimicrobial peptides (STAMPs) were successfully developed. The Phase- II studies aim to optimize, improve and perfect these promising molecules into actual therapeutic products against oral microbial infections. The Specific Aims are: 1): Anti-S. mutans STAMPs will be optimized for stronger killing ability, higher binding affinity, smaller size and suitable stability in saliva; 2) Extensive cellular toxicity, genetic toxicity, and animal toxicity studies will be performed to examine the safety issue of the anti-S. mutans STAMPs; and 3) The effective and safe anti-S. mutans STAMPs will be chosen to test their ability to convert the "diseased plaque" to "healthy plaque", using the established in vitro, ex vivo and in vivo assays developed in UCLA, Colgate-Palmolive and C3 Jian Inc. The successful execution of this research plan will further improve the STAMP technology and lead to the development of a targeted antimicrobial therapy against cariogenic bacterium Streptococcus mutans. Phase III follow up works will include human clinical trials to evaluate the safety and efficacy of these STAMP-based therapeutic agents. [unreadable] [unreadable] [unreadable]